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Glycobiology Advance Access published online on February 24, 2009
Glycobiology, doi:10.1093/glycob/cwp022
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells

Davide Vigetti*,#, Manuela Rizzi*,#, Manuela Viola*, Eugenia Karousou*, Anna Genasetti*, Moira Clerici*, Barbara Bartolini*, Vincent C. Hascall§, Giancarlo De Luca* and Alberto Passi*,¶

* Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell’Insubria, via J.H. Dunant 5, 21100 Varese, Italy
§ Biomedical Engineering ND20, The Cleveland Clinic, Cleveland, Ohio 44195, USA

Correspondence to: prof. Alberto Passi, Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell’Insubria, via J.H. Dunant 5, 21100 Varese, Italy. Phone ++39 0332 217140, Fax ++39 0332 217119, email: alberto.passi{at}uninsubria.it

Received on July 18, 2008; accepted on February 3, 2009

Extracellular matrix (ECM) remodelling after proatherosclerotic injury involves an increase in hyaluronan (HA) that is coupled with vascular smooth muscle cell (SMC) migration, proliferation, and to neointima formation. As such events are dependent on HA, in this study we assessed the effects on SMC behavior of 4-methylumbelliferone (4-MU). As previously described in other cell types, 4-MU reduced HA in cultures of primary human aortic SMCs (AoSMCs) as well as the cellular content of the HA precursor UDP-glucuronic acid. We found that SMCs increased UDP-glucuronyl transferase 1 (UGT1) enzymes, which can reduce the cellular content of UDP-glucuronic acid confirming that the availability of the UDP-sugar substrates can regulate HA synthesis. Interestingly, we reported that 4-MU reduced the transcripts coding for the three HA synthases (HAS) as well as UDP glucose pyrophosphorylase and dehydrogenase. As HAS transcript reduction is common to other cell types, 4-MU effect on gene expression may be considered a mechanism for HA synthesis inhibition. Moreover, we showed that 4-MU strongly inhibits AoSMCs migration, which was restored by addition of exogenous HA indicating that the rescuing depends on the interaction of HA with its receptor CD44. Besides the decrease in HA synthesis and cell migration, 4-MU reduced AoSMCs proliferation, indicating that 4-MU may exert a vasoprotective effect.

Key words: atherosclerosis / neointima / Vascular pathology / UDP-sugars

# Both authors contributed equally to this work.


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